Chronic rhinosinusitis (CRS) affects 16% of the United States' population with few proven treatments. CRS with nasal polyps (CRSwNP) is the most difficult form of the disease to treat and has a negative impact on quality of life that exceeds other chronic conditions, such as heart failure and chronic obstructive pulmonary disease. CRSwNP is characterized by a type 2 skewed inflammatory profile and increased numbers of sinonasal fibroblasts. Given its anti-inflammatory properties, vitamin D3 (VD3) may serve as a potential novel treatment for CRSwNP. We have shown that patients with CRSwNP have alterations to the vitamin D system that extends beyond a simple nutrient deficiency caused by diet or lifestyle. CRSwNP patients have reduced sinonasal levels of the active metabolite of VD3, 1,25(OH)2D3, despite adequate circulating forms of its precursors or 1,25(OH)2D3 itself. Furthermore, reductions in human sinonasal epithelial cell (HSNEC) levels of 1?-hydroxylase, the enzyme responsible for the final hydroxylation to make 1,25(OH)2D3, is associated with more severe CRSwNP. The scientific premise of these studies is to determine if increasing local levels of 1,25(OH)2D3 can reduce sinonasal inflammation and serve as a potential treatment for CRSwNP. In preliminary studies, we observed that 1,25(OH)2D3 reduced human sinonasal epithelial cell (HSNEC) and sinonasal fibroblast (HSNF) production of type 2 mediators. While HSNF can respond to 1,25(OH)2D3, they are not capable of metabolizing it themselves, leaving them dependent on other cell types, mainly HSNECs, as a source of 1,25(OH)2D3. Based on these and other data, we hypothesize that impaired 25(OH)D3 metabolism by HSNECs results in local deficiencies in 1,25(OH)2D3, thereby driving the type 2 inflammation and fibroblast activation associated with CRSwNP. We will test this hypothesis through the execution of the following aims. Aim 1 will examine the contribution of 25(OH)D3 metabolism to HSNEC-derived inflammation and determine the ability of 1,25(OH)2D3 to modulate endogenous and exogenously-stimulated inflammation by control and CRSwNP HSNECs. In Aim 2 we will determine the role of human sinonasal epithelial 25(OH)D3 metabolism and 1,25(OH)2D3 in the regulation of fibroblast-derived inflammation. In Aim 3 we will test, in vivo, how alterations in sinonasal vitamin D metabolism regulates inflammation and disease severity utilizing a murine model of atopic CRS. With respect to outcomes, these studies will greatly expand our understanding of how local 25(OH)D3 metabolism regulates sinonasal inflammation and will test the feasibility and potential efficacy of sinonasal delivery of 1,25(OH)2D3 as a treatment for CRSwNP. In addition to the direct applicability of these findings to CRSwNP, our results may be relevant to other respiratory diseases, most notably to asthma and allergic rhinitis.